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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0900947v1 183/4/2659    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Aagaard, C. S. Articles by Andersen, P. PubMed PubMed Citation Articles by Aagaard, C. S. Articles by Andersen, P. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Tuberculosis

Quality and Vaccine Efficacy of CD4⁺ T Cell Responses Directed to Dominant and Subdominant Epitopes in ESAT-6 from Mycobacterium tuberculosis¹

Department of Infectious Immunology, Statens Serum Institute, Copenhagen, Denmark

The ESAT-6 (early secretory antigenic target) molecule is a very important target for T cell recognition during infection with Mycobacterium tuberculosis. Although ESAT-6 contains numerous potential T cell epitopes, the immune response during infection is often focused toward a few immunodominant epitopes. By immunization with individual overlapping synthetic peptides in cationic liposomes (cationic adjuvant formulation, CAF01) we demonstrate that the ESAT-6 molecule contains several subdominant epitopes that are not recognized in H-2^d/b mice either during tuberculosis infection or after immunization with ESAT-6/CAF01. Immunization with a truncated ESAT-6 molecule (15ESAT-6) that lacks the immunodominant ESAT-6_1–15 epitope refocuses the response to include T cells directed to these subdominant epitopes. After aerosol infection of immunized mice, T cells directed to both dominant (ESAT-6-immunized) and subdominant epitopes (15ESAT-6-immunized) proliferate and are recruited to the lung. The vaccine-promoted response consists mainly of double- (TNF- and IL-2) or triple-positive (IFN-, TNF-, and IL-2) polyfunctional T cells. This polyfunctional quality of the CD4⁺ T cell response is maintained unchanged even during the later stages of infection, whereas the naturally occurring infection stimulates a response to the ESAT-6_1–15 epitope that consist almost exclusively of CD4⁺ effector T cells. ESAT-6 and 15ESAT-6 both give significant protection against aerosol challenge with tuberculosis, but the most efficient protection against pulmonary infection is mediated by the subdominant T cell repertoire primed by 15ESAT-6.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Tuberculosis Vaccine Cluster-European Commission (TBVac-EC) Grant CT2003-503367.

² Address correspondence and reprint requests to Dr. Claus S. Aagaard and Dr. Peter Andersen, Department of Infectious Immunology, Statens Serum Institute, Artillerivej 5, 2300 Copenhagen, Denmark. E-mail addresses: caa{at}ssi.dk and pa{at}ssi.dk

³ Abbreviations used in this paper: MTB, Mycobacterium tuberculosis; BCG, bacillus Calmette-Guérin; CAF, cationic adjuvant formulation; ESAT, early secretory antigenic target; MFI, mean fluorescence intensity.